Despite several decades of research, our understanding of the role that vitamin E, specifically a-tocopherol, plays in health and disease remains quite limited. The importance of a-tocopherol in maintaining neuromuscular health was first elucidated by the discovery that mutations in the gene encoding a-tocopherol transfer protein (TTPA) cause ataxia with vitamin E deficiency in humans. Other inherited conditions that affect a-tocopherol transport and metabolism lead to distinct forms of neuroaxonal dystrophy (NAD), which result in devastating progressive neurodegenerative disease. However, phenotypes resembling ataxia with vitamin E deficiency have been described that are not associated with mutations of TTPA, and much remains unknown about the molecular pathogenesis of a-tocopherol-associated NAD. Naturally occurring domestic animal models of NAD are impacted by tissue a-tocopherol levels and have striking histopathologic similarities to ataxia with vitamin E deficiency in humans. A comparative medicine approach may be the key to unraveling the pathophysiologic basis for this a-tocopherol-associated NAD. The overall goal of my research is to employ a multi-disciplinary comparative approach to discover novel mechanisms responsible for NAD. A laboratory mouse model and a naturally occurring large animal model exist for alpha-tocopherol associated NAD. My overall hypothesis is that the mechanism of alpha-T-associated neurodegeneration in murine and equine models of NAD arises from the temporal interaction between mutations in genes involved in alpha-T transport or metabolism and dietary alpha-T concentrations during post-natal development. Additionally, I hypothesize that the similarity in these forms of alpha-T-associated neurodegeneration will be further illustrated by a significant and temporally progressive downregulation of genes associated with presynaptic function, namely complexin 2 and vamp2. This proposal drives two specific aims targeted at uncovering the molecular mechanisms responsible for alpha-tocopherol associated NAD. By defining the temporal gene expression patterns in the Ttpa-deficient mouse while simultaneously uncovering variations of gene regulation and dysregulation in the naturally-occurring equine NAD model, novel comparative mechanisms for NAD will be identified and the role of vitamin E in neurodegeneration further defined. The K01 award would support Dr. Carrie Finno's career development as a postdoctoral DVM, PhD and prepare her for independent research in an academic environment. Dr. Finno has a keen interest in comparative genomics of neurodegenerative disorders and a desire to gain expertise in specialized pathologic techniques, transcriptomics and advanced biomedical research. Experience using mouse model will enhance Dr. Finno's future research potential. Five years of mentored support is requested.